31. PARP inhibitor olaparib has a potential to increase the effectiveness of electrochemotherapy in BRCA1 mutated breast cancer in miceMaša Omerzel, Tanja Jesenko, Boštjan Markelc, Larisa Janžič, Maja Čemažar, Gregor Serša, 2021, original scientific article Abstract: Electrochemotherapy (ECT), a local therapy, has different effectiveness among tumor types. In breast can-cer, its effectiveness is low; therefore, combined therapies are needed. The aim of our study was to com-bine ECT with PARP inhibitor olaparib, which could inhibit the repair of bleomycin or cisplatin inducedDNA damage and potentiate the effectiveness of ECT. The effects of combined therapy were studied inBRCA1mutated (HCC1937) and non-mutated (HCC1143) triple negative breast cancer cell lines.Therapeutic effectiveness was studied in 2D and 3D cell cultures andin vivoon subcutaneousHCC1937 tumor model in mice. The underlying mechanism of combined therapy was determined withthe evaluation ofcH2AX foci. Combined therapy of ECT with bleomycin and olaparib potentiated theeffectiveness of ECT inBRCA1mutated HCC1937, but not in non-mutated HCC1143 cells. The combinedtherapy had a synergistic effect, which was due to the increased number of DNA double strand breaks.Addition of olaparib to ECT with bleomycinin vivoin HCC1937 tumor model had only minimal effect,indicating repetitive olaparib treatment would be needed. This study demonstrates that DNA repar inhibiting drugs, like olaparib, have the potential to increase the effectiveness of ECT with bleomycin.
Keywords: electrochemotherapy, breast cancer, olaparib, bleomycin
Published in DiRROS: 21.09.2022; Views: 515; Downloads: 179
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32. BAP1-defficient breast cancer in a patient with BAP1 cancer syndromeAna Blatnik, Domen Ribnikar, Vita Šetrajčič Dragoš, Srdjan Novaković, Vida Stegel, Biljana Grčar-Kuzmanov, Nina Boc, Barbara Perić, Petra Škerl, Gašper Klančar, Mateja Krajc, 2022, original scientific article Abstract: BAP1 cancer syndrome is a rare and highly penetrant hereditary cancer predisposition. Uveal melanoma, mesothelioma, renal cell carcinoma (RCC) and cutaneous melanoma are considered BAP1 cancer syndrome core cancers, whereas association with breast cancer has previously been suggested but not confirmed so far. In view of BAP1 immunomodulatory functions, BAP1 alterations could prove useful as possible biomarkers of response to immunotherapy in patients with BAP1-associated cancers. We present a case of a patient with BAP1 cancer syndrome who developed a metastatic breast cancer with loss of BAP1 demonstrated on immunohistochemistry. She carried a germline BAP1 likely pathogenic variant (c.898_899delAG p.(Arg300Glyfs*6)). In addition, tumor tissue sequencing identified a concurrent somatic variant in BAP1 (partial deletion of exon 12) and a low tumor mutational burden. As her triple negative tumor was shown to be PD-L1 positive, the patient was treated with combination of atezolizumab and nab-paclitaxel. She had a complete and sustained response to immunotherapy even after discontinuation of nab-paclitaxel. This case strengthens the evidence for including breast cancer in the BAP1 cancer syndrome tumor spectrum with implications for future cancer prevention programs. It also indicates immune checkpoint inhibitors might prove to be an effective treatment for BAP1-deficient breast cancer.
Keywords: BAP1, breast cancer, hereditary cancer syndromes, immunotherapy
Published in DiRROS: 19.09.2022; Views: 448; Downloads: 181
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33. Real-world testing practices, treatment patterns and clinical outcomes in patients from Central Eastern Europe with EGFR-mutated advanced non-small cell lung cancer : a retrospective chart review study (REFLECT)Urška Janžič, Nina Turnšek, Mircea Dediu, Ivan Shterev Donev, Roxana Lupu, Gabriela Teodorescu, Tudor Ciuleanu, Adam Płużański, 2022, original scientific article Abstract: The targeted therapy with tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor mutation (EGFRm) in advanced non-small cell lung cancer (NSCLC) changed the treatment paradigm. REFLECT study (NCT04031898) explored EGFR/T790M testing and treatment patterns in EGFRm NSCLC patients receiving first- or second-generation (1G/2G) EGFR TKIs as front-line (1L) in eight countries. Pooled data from Central Eastern Europe (CEE) countries from this study (Bulgaria, Poland, Romania, Slovenia) are presented here. This physician-led chart review study was conducted in patients with confirmed-EGFRm NSCLC initiating 1L 1G/2G EGFR TKIs between 2015–2018. The CEE cohort included 389 patients receiving 1L erlotinib (37%), afatinib (34%), and gefitinib (29%). Overall, 320 (82%) patients discontinued 1L, and 298 (77%) progression events were registered. Median progression free survival on 1L TKIs was 14.0 (95% CI: 12.6–15.6) months. Median overall survival from 1L start was 26.6 (95% CI: 24.1–29.0) months. Attrition rate between 1L and next line was 30%. Among patients with 1L progression, 200 (67%) were tested for T790M and 58% were positive. This first CEE analysis of treatments and outcomes in EGFRm NSCLC patients highlights the importance of using the most efficacious therapies currently available in 1L to reduce attrition and improve patient outcomes.
Keywords: lung neoplasms, non-small cell lung carcinoma, Eastern Europe, real-world study, REFLECT study, epidermal growth factor receptor, lung cancer
Published in DiRROS: 09.09.2022; Views: 492; Downloads: 201
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34. Identification of spliceogenic variants beyond canonical GT-AG splice sites in hereditary cancer genesVita Šetrajčič Dragoš, Ksenija Strojnik, Gašper Klančar, Petra Škerl, Vida Stegel, Ana Blatnik, Marta Banjac, Mateja Krajc, Srdjan Novaković, 2022, original scientific article Abstract: Pathogenic/likely pathogenic variants in susceptibility genes that interrupt RNA splicing are a well-documented mechanism of hereditary cancer syndromes development. However, if RNA studies are not performed, most of the variants beyond the canonical GT-AG splice site are characterized as variants of uncertain significance (VUS). To decrease the VUS burden, we have bioinformatically evaluated all novel VUS detected in 732 consecutive patients tested in the routine genetic counseling process. Twelve VUS that were predicted to cause splicing defects were selected for mRNA analysis. Here, we report a functional characterization of 12 variants located beyond the first two intronic nucleotides using RNAseq in APC, ATM, FH, LZTR1, MSH6, PALB2, RAD51C, and TP53 genes. Based on the analysis of mRNA, we have successfully reclassified 50% of investigated variants. 25% of variants were downgraded to likely benign, whereas 25% were upgraded to likely pathogenic leading to improved clinical management of the patient and the family members.
Keywords: hereditary cancer, RNA sequencing, spliceogenic
Published in DiRROS: 07.09.2022; Views: 467; Downloads: 240
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35. Neuroendocrine carcinoma of the larynx and pharynx : a clinical and histopathological studyPrimož Strojan, Robert Šifrer, Alfio Ferlito, Cvetka Grašič-Kuhar, Boštjan Lanišnik, Gaber Plavc, Nina Zidar, 2021, original scientific article Abstract: Neuroendocrine carcinomas (NECs) of the head and neck are rare and the experience scanty. The Cancer Registry of Slovenia database was used to identify cases of laryngeal and pharyngeal NECs diagnosed between 1995%2020. Biopsies were analyzed for the expression of standard neuroendocrine markers (synaptophysin, chromogranin, CD56), INSM1, Ki-67, p16, and PD-L1 (using the combined positive score, CPS). In situ hybridization for human papillomavirus (HPV) and Epstein%Barr virus (EBV) was performed. Twenty patients (larynx, 12; pharynx, 8) were identified. One tumor was well differentiated (WD), five were moderately differentiated (MD), and 14 were poorly differentiated (PD). Disease control was achieved solely by surgery in 4/4 MD/PD T1-2N0-1 tumors. Eight patients died of the disease, seven of which were due to distant metastases. All three traditional markers were positive in 11/17 NECs and the INSM1 marker in all 20 tumors. Two of fourteen p16-positive tumors were HPV-positive, but all three nasopharyngeal NECs were EBV-negative. Three tumors had CPSs % 1. In conclusion, INSM1 was confirmed to be a reliable marker of neuroendocrine differentiation. Except in WD and early-stage MD/PD tumors, aggressive multimodal therapy is needed; the optimal systemic therapy remains to be determined. p16, HPV, and EBV seem to bear no prognostic information.
Keywords: electrochemotherapy, head and neck cancer, neuroendocrinic carcinoma
Published in DiRROS: 07.09.2022; Views: 480; Downloads: 217
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36. Real-world data on detection of germline and somatic pathogenic/likely pathogenic variants in BRCA1/2 and other susceptibility genes in ovarian cancer patients using next generation sequencingVida Stegel, Ana Blatnik, Erik Škof, Vita Šetrajčič Dragoš, Mateja Krajc, Brigita Gregorčič, Petra Škerl, Ksenija Strojnik, Gašper Klančar, Marta Banjac, Janez Žgajnar, Maja Ravnik-Oblak, Srdjan Novaković, 2022, original scientific article Abstract: Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients.
Keywords: BRCA, ovarian cancer, tumor genotyping, HBOC
Published in DiRROS: 06.09.2022; Views: 509; Downloads: 277
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37. Cancer patients’ survival according to socioeconomic environment in a high-income country with universal health coverageVesna Zadnik, Tina Žagar, Sonja Tomšič, Ana Mihor, Katarina Lokar, 2022, original scientific article Abstract: Despite having an established systematic approach to population survival estimation in Slovenia, the influence of socioeconomic environment on cancer patients’ survival has not yet been evaluated. Thus, the main aim of our study was to quantify the potential impact of socioeconomic environment on cancer patients’ survival in our population in the 21st century. The net survival was calculated and stratified into quintiles of Slovenian version of the European Deprivation Index for all adult cancer patients diagnosed between 2004 and 2018 using the national cancer registry data. After accounting for basic demographic variables (age and gender), differences in stage at diagnosis, as well as the impact of the cancer treatment improvements over time, we found that cancer patients in Slovenia with lower socioeconomic status experience worse survival and have higher mortality. In particular, the odds of dying from oral, stomach, colorectal, liver, pancreatic, lung, breast, ovarian, corpus uteri, prostate, and bladder cancers, as well as for melanoma, leukemia, and non-Hodgkin lymphoma, are significantly higher in the socioeconomically most deprived group of patients compared to the most affluent group. The inequalities in cancer burden we found could help decision-makers to better understand the magnitude of this problem.
Keywords: cancer, population-survival, socioeconomic deprivation, cancer registry
Published in DiRROS: 06.09.2022; Views: 436; Downloads: 247
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39. Solid cancer patients achieve adequate immunogenicity and low rate of severe adverse events after SARS-CoV-2 vaccinationUrška Janžič, Urška Bidovec, Katja Mohorčič, Loredana Mrak, Nina Fokter Dovnik, Marija Ivanović, Maja Ravnik, Marina Čakš, Erik Škof, Jerneja Debeljak, Peter Korošec, Matija Rijavec, 2022, original scientific article Abstract: Background: SARS-CoV-2 vaccination in cancer patients is crucial to prevent severe COVID-19 disease course. Methods: This study assessed immunogenicity of cancer patients on active treatment receiving mRNA-based SARS-CoV-2 vaccine by detection of anti-SARS-CoV-2 S1 IgG antibodies in serum, before, after the first and second doses and 3 months after a complete primary course of vaccination. Results were compared with healthy controls. Results: Of 112 patients, the seroconversion rate was 96%. A significant reduction in antibody levels was observed 3 months after vaccination in patients receiving immune checkpoint inhibitors versus control participants (p < 0.001). Adverse events were mostly mild. Conclusion: Immunogenicity after mRNA-based vaccine in cancer patients is adequate but influenced by the type of anticancer therapy. Antibody levels decline after 3 months, and thus a third vaccination is warranted.
Keywords: onkološko zdravljenje, imunogenost, osnovno cepljenje mRNA, čvrsti tumorji, anticancer treatment, immunogenicity, mRNA-based vaccination, solid cancer
Published in DiRROS: 24.06.2022; Views: 792; Downloads: 329
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40. Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platformMarie Morfouace, Silvia Novello, A. Stevovic, C. Dooms, Urška Janžič, Thierry Berghmans, Rafal Dziadziuszko, T. Gorlia, Enriqueta Felip, Benjamin Besse, 2022, original scientific article Abstract: Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.
Keywords: thoracic neoplasms -- Europe, lung neoplasms -- Europe, diagnostic screening programs -- Europe, malignancies, lung cancer
Published in DiRROS: 24.06.2022; Views: 700; Downloads: 486
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